Charcot-Marie-Tooth (CMT) disease affects approximately one in 2500 individuals and is the most common inherited disorder of the peripheral nervous system.1,2 Clinically, CMT patients show slowly progressive distal muscle weakness and atrophy, foot deformities, steppage gait, distal sensory loss, and decreased or absent deep tendon reflexes.1,2 Electrophysiologically, CMT is divided into three groups: demyelinating CMT (type 1), CMT characterized by axonal loss (type 2), and intermediate forms demonstrating signs of both demyelination and axonal loss. In cases where the disease exclusively affects motor axons and sensory involvement is absent, both clinically and electrophysiologically, the condition is referred to as distal Hereditary Motor Neuropathy (distal HMN). Thus far, CMT and distal HMN have been associated with approximately 40 causative genes (for an overview, see the World Wide Web at molgen.ua.ac.be/CMTMutations) and the pattern of inheritance can be autosomal dominant, autosomal recessive or X-linked.1,2 The underlying pathological mechanism for most of the mutated genes remains unknown.
Mutations in the gene encoding the 27 kDa small heat-shock protein (HSPB1, also called HSP27) on chromosome 7q11.23 were previously identified as a cause of CMT2 and/or distal HMN2.3,4 HSPB1 is a member of the small heat-shock proteins that contain a highly conserved α-crystallin domain. HSPB1 shows chaperone activity by binding to misfolded and/or (partially) denatured proteins and preventing them from forming toxic aggregates.5,6 In addition, HSPB1 also plays a crucial role in diverse cellular processes such as modulation of the intracellular redox state, the assembly of cytoskeletal structures, cell differentiation, and inhibition of apoptosis by interacting with pro-apoptotic signaling proteins.5-7 
So far, eleven missense mutations have been identified in HSPB1 that are all associated with CMT2 and/or distal HMN. Seven of these mutations are located in the α-crystallin domain (including S135F), two in the N-terminal part and two targeting the same amino acid (P182L/S) in the short C-terminal tail of the protein.3,8-11 All these mutations are inherited autosomal dominantly, except one (L99M) that shows an autosomal recessive pattern of inheritance.3,8-11 Depending on the mutation, patients show either CMT2 or distal HMN symptoms. The S135F mutation is the only one that causes both CMT2 and distal HMN.3 Thus far, there is no cure for CMT disease, and any possible therapy would be most welcomed.